Abstract: www.nature.com/scientificreports
OPEN
Quercetin inhibited LPS‑induced
cytokine storm by interacting
with the AKT1‑FoxO1
and Keap1‑Nrf2 signaling pathway
in macrophages
Jingyi Xu 1,5, Yue Li 1,5, Xi Yang 2,5, Hong Li 1, Xi Xiao 1, Jia You 2, Huawei Li 3, Lingnan Zheng 2,
Cheng Yi 2*, Zhaojun Li 4* & Ying Huang 1*
Cytokine storm (CS) emerges as an exacerbated inflammatory response triggered by various factors
such as pathogens and excessive immunotherapy, posing a significant threat to life if left unchecked.
Quercetin, a monomer found in traditional Chinese medicine, exhibits notable anti-inflammatory
and antiviral properties. This study endeavors to explore whether quercetin intervention could
mitigate CS through a combination of network pharmacology analysis and experimental validation.
First, common target genes and potential mechanisms affected by quercetin and CS were identified
through network pharmacology, and molecular docking experiments confirmed quercetin and core
targets. Subsequently, in vitro experiments of Raw264.7 cells stimulated by lipopolysaccharide (LPS)
showed that quercetin could effectively inhibit the overexpression of pro-inflammatory mediators and
regulate the AKT1-FoxO1 signaling pathway. At the same time, quercetin can reduce ROS through the
Keap1-Nrf2 signaling pathway. In addition, in vivo studies of C57BL/6 mice injected with LPS further
confirmed quercetin’s inhibitory effect on CS. In conclusion, this investigation elucidated novel target
genes and signaling pathways implicated in the therapeutic effects of quercetin on CS. Moreover,
it provided compelling evidence supporting the efficacy of quercetin in reversing LPS-induced CS,
primarily through the regulation of the AKT1-FoxO1 and Keap1-Nrf2 signaling pathways.
Keywords Cytokine storm, Macrophages, Network pharmacology, Quercetin, AKT1-FoxO1 pathway,
Keap1-Nrf2 pathway
Abbreviations
BALF Bronchoalveolar lavage fluid
BP Biological process
CC Cellular composition
COVID-19 Coronavirus disease 2019
CS Cytokine storm
DEX Dexamethasone
DMSO Dimethyl sulphoxide
FoxO Forkhead box proteins O
GO Gene ontology
IL-6 Interleukin-6
1
West China School of Basic Medical Science and Forensic Medicine, Sichuan University, No.17, Section3,
Renmin South Road, Chengdu 610044, People’s Republic of China. 2Department of Medical Oncology, West
China Hospital, Cancer Center, Sichuan University, No.37 Guoxue Lane, Chengdu 610041, China. 3Department
of Integrated Traditional Chinese and Western Medicine, School of Medicine, Cancer Hospital, University of
Electronic Science and Technology of China, Chengdu 610041, China. 4Department of Radiation Oncology, Hainan
Affiliated Hospital of Hainan Medical University (Hainan General Hospital), No.31, Longhua Road, Haikou 570100,
China. 5These authors contributed equally: Jingyi Xu, Yue Li and Xi Yang. *email: yicheng6834@126.com;
lzjradiotherapy@163.com; huangying68@163.com
Scientific Reports |
(2024) 14:20913
| https://doi.org/10.1038/s41598-024-71569-y
1
Vol.:(0123456789)
www.nature.com/scientificreports/
iNOS Inducible nitric oxide synthase
Keap1 Kelch-like ECH-associated protein 1
KEGG Kyoto encyclopedia of genes and genomes
LPS Lipopolysaccharides
MCP-1 Monocyte chemotactic protein 1
MF Molecular function
NO Nitric oxide
Nrf2 Nuclear factor erythroid 2-related factor
PPI Protein–protein interaction network
ROS Reactive oxygen species
TCM Traditional Chinese medicine
TNF-α Tumor necrosis factor..
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